This invention relates to a device and method for determining and monitoring concentration levels of one or more constituents within a varying in time, complex multi component structure, (for example blood constituents in blood sample, tissue or body parts) or, in particular, blood and tissue constituents in living subjects such as humans or animals.
The application of spectroscopy for chemical analysis is well known. For many years, however, it was mainly used for atomic analysis because sufficiently sensitive detectors did not exist for infrared, where information on vibration states of the molecules (especially those of organic origin) is located. Advances in technology of IR detectors have dramatically changed the situation and presently a large number of detectors, instruments and methods exist for such applications. This has also opened the way for new applications, but has imposed new requirements on the technology. One of the most important applications is a noninvasive analysis of chemical compositions of living subjects.
It is generally appreciated that light in spectral range 500 nm to 770 nm belongs to the visible part of the spectrum but, since it does not cover whole visible range and it is directly adjacent to the infrared part of the spectrum, herein it is referred to as adjacent visible (AV). It is widely accepted that of the infrared part of the electromagnetic spectrum (IR) is divided into the near infrared (NIR), which expands beyond the visible to about 2700 nm, the middle infrared radiation (MIR), which expands beyond the NIR range and a further expanding far infrared range (FIR). There are some photodetectors (mainly silicon) whose sensitivity covers the visible part of spectrum and initial part of NIR. Therefore, part of visible range adjacent to NIR and part of NIR adjacent to visible will be referred here as AV/NIR, while the remaining part of NIR range will be referred to as the xe2x80x9clonger wavelength NIR regionxe2x80x9d or xe2x80x9cLWNIRxe2x80x9d.
Non-Invasive Techniques
Previous devices for non-invasively monitoring concentration of blood constituents of a patient are known. Usually, a sensor is used to externally measure either the concentration of the constituents in gases emitted by the body or contained in the perspiration, or the concentration of the constituents contained in body fluids such as tears, saliva, or urine. Alternatively, the blood constituents are identified by measurement of attenuation of some radiation passed through a part of a patient""s body such as an earlobe, a finger or skin. In majority cases, radiation is measured at one, two or limited number of relatively narrow spectral bands obtained from separate, narrow band light sources (see for example U.S. Pat. No. 4,655,225; U.S. Pat. No. 4,883,953; and U.S. Pat. No. 4,882,492). Some of these devices perform measurements at limited number relatively narrow spectral bands consecutively selected from spectrally broad light by a set of exchangeable narrow-band spectral filters. Analysis of absolute and relative changes in light intensity at these bands under certain conditions may provide important information on body constituents. Exchange of the filters and time required for their stabilization to obtain precise measurement, very often significantly increase duration of the measurement process and as a result, the measurement in different bands are taken with significant time delays. Because of physiological variability of physical state of the alive person, this leads to situation when measurements at different wavelengths are taken under changed physical conditions of the body, making impossible to measure the constituents of the body. Another source of the error in the systems with limited number of discrete spectral bands is wavelength shift of the selected bands from measurement to the measurement and from instrument to the instrument. There are some medical and other applications when these two sources of the error make measurement of constituents impossible. In such a case it becomes important to make the measurement in whole spectrum virtually simultaneously and to preserve as complete as possible information on whole spectrum. This is achieved applying other techniques, which measure either a full spectrum of light interacting with sample, with a large number (for example, 128 or 256) of wavelengths in a specific range and those that measure a limited number of wavelengths. Those that measure full spectra typically use the wavelengths in the AV/NIR range (see for examples U.S. Pat. No. 5,361,758 and U.S. Pat. No. 4,975,581), where arrays of the photodetectors, produced with application of well established silicon technology, have been available for long time for simultaneous registration of the spectra in large number of discrete points. There are several advantages in measurement of whole spectrum. One of them consists in that the spectra provide information about the desired analyte as well as information about interfering substances (e.g., other analytes) and effects (e.g., light scattering). The second advantage is capability to register a complete information on spectrum even if it is shifted due to temperature changes of sample. Finally, the third advantage is that even if the instrument loses wavelength calibration, whole information is still preserved in the spectrum and can be easily extracted once new wavelength calibration data is available. In some cases, however, there is not enough information available in the above range or available information is insufficient for precise measurement of body constituents and additional information outside the above mentioned spectral range (usually at longer wavelengths) is required.
In some cases, the methods that take measurements at limited number of wavelengths only within the 1100 to 1700 nm region can be sufficient, because of the sharper analyte spectra that exist in this region. In majority cases, however, while they provide information relating to the analyte of interest, there is not enough independent information on other analytes whose absorption spectra interferes with that of the desired analyte. In some cases additional information obtained in earlier mentioned spectral range 580 nm to 1100 nm helps to eliminate ambiguity introduced by interfering analytes. It is clear that if the sample demonstrates a temporal variability, a simultaneous measurement in whole spectral range of the interest is preferred, to eliminate possible errors caused by changes in the sample.
Furthermore, as in earlier discussed cases for shorter spectral range, spectral measurement in limited number of points within 1100 nm to 1700 nm spectral range in some cases may not be sufficient for recognition of desired analyte. In addition, the measurements usually are very sensitive to both: variations of spectral position of the selected points and width and shape of spectral bands measured at those points. Thus, the methods when measurement in different parts of spectrum are taken at different time, or from different part of samples or within limited number of points may not be sufficient for precise analysis of constituents of the samples and more advanced instruments are required. The way to eliminate these limitations and provide instrument suitable for such measurements is given it this invention. Overall, previous non-invasive devices and techniques have not been sufficiently accurate to be used in place of invasive techniques in the measurement of blood constituent concentration in patients. Some of them have been designed to measure one component only and physical changes to the instrument have to be applied to adapt them to measurement of different components. For some devices it takes unreasonably long time to produce a results; or, some other cannot produce results in an easy-to-use form; or, they cannot measure concentration of two or more constituents simultaneously. Obviously, if the device gives an inaccurate reading, disastrous results could occur for the patient using the device to calculate, for example, dosages for insulin administration.
It has been recognized that simultaneous spectrum collection is possible only by applying a large number of photodetectors. Technically this is brought about by spatial dispersion of radiation, composed of different wavelengths, by means of a dispersing device (diffraction grating, for example) and registration of its intensity with an array of photodetectors. In such cases, the signal registered by each detector of the array can be read virtually simultaneously. This technique has been recognized and many spectrometers with an array of photodetectors are available on the market. Unfortunately, the available arrays systems have various limitations, therefore, the capabilities of such spectrometers are limited.
The most important limitation for each array is its sensitivity range, which is determined by the material used to produce an array. The sensitivity range determines in what spectral range the instrument built with an application of a particular array can work. Grating spectrometers designed with the application of arrays of photodetectors have further intrinsic limitations, which put even stronger constrains on the performance of the instruments. One such constraint is the existence of additional diffraction orders in light diffracted by a grating. The existence of the second order imposes the condition that the spectral range of an array-based instrument cannot be wider than one octave, unless a special filter is placed in front of the array. Production of such filters is not easy, hence, instruments are built to cover less than one octave and a cut-off filter, eliminating radiation with shorter wavelengths is normally used to eliminate the impact of that order. As a result, the spectral range of existing array-based instruments is such that the longest measured wavelength of analyzed light is always smaller than the doubled length of the shortest wavelength analyzed by the spectrometer
Finally, since the number of elements in an array and length of an array are limited, very often it is impossible to achieve high resolution even in that limited spectral range. As a result, the performance of array-based instruments is a compromise between such factors and consequently spectrometers very often cannot provide information needed for particular applications. If, in addition, these applications require simultaneous registration of the wider spectrum (as, for example, non-invasive in-vivo diagnostic), the measurement problem remains unsolved.
While for some applications relatively simple instruments, measuring of infrared radiation at one or small number of wavelengths are sufficient, it was discovered that for more demanding applications, such as, for example, glucose concentration in blood in a human body, significantly more advanced instruments are required. In particular it has been found that for such applications it is important to collect data in a wide spectral range covering at least part of near infrared and adjacent to it visible part of the spectrum. It has been also discovered that for living subject it is crucial that information is collected simultaneously in whole spectral -range of the interest, otherwise physiological changes in the organism during measurement may significantly contribute to the measurement error. Finally, it has been found that because of dependence of the molecular vibration spectrum on temperature it is important to have as complete information on the spectrum as possible. Therefore a need has arisen to build a spectroscopic system able to simultaneously collect information in as wide spectrum as possible. This approach excludes techniques when a spectrum of light is collected with the application of any scanning instrument like those with rotated gratings or Fourier transform spectrometers.
Accordingly, the present invention provides a method for monitoring the concentration level of a particular constituent in a sample or, alternatively, of measuring the concentration level of one or more different constituents using a non-invasive device with higher precision and in a short period of time, through simultaneous measurement of light signal in several different spectral ranges using separate array-based spectrometers.
The present inventors have determined that analyte measurement accuracy with spectral devices measuring full spectra absorption/reflectance in the AV/NIR region, is enhanced by adding to such measurement, measurements from one or more arrays of wavelength in the infrared region
In its broad aspect the present invention provides a method for monitoring the concentration level of a constituent in sample comprising placing the sample in a non-invasive device capable of emitting radiation; directing the radiation onto the sample; measuring radiation collected from the sample; calculating the concentration level based on the measured radiation wherein the radiation directed onto the tissue and collected from the tissue is of the wavelengths starting at 500 nm and expanding into AV/NIR range, and wavelengths in the LIR range possible from 1100 to 1700 nm.
According to one embodiment, the present invention provides a method for measuring concentration levels of blood constituents within a living subject such as humans or animals, wherein, a polychromatic light source or other single or multiplicity of radiation sources are used that emit a broad spectrum of light in the required range. A number of spectrum analyzing systems containing photodetector arrays, possible sensitive in different spectral ranges provide sensitivity and resolution over portions of the range of the interest, preferably one from 500-1100 nm and one from 900-1700 nm and further spectral ranges. The method comprises the steps of:
directing light at a continuum wavelengths (whether from one or more sources) simultaneously onto a sample or a part of a subject;
collecting the continuum of light after the light has been directed onto and interacted with the sample or the part;
dividing of collected light into at least two parts separately directed to the corresponding number of spectrum analyzing systems, at least one for AV/NIR and at least another one for WNIR,
forming of each part of light into a light beam, suitable for simultaneous analysis of corresponding spectral content of each part, preferably by means of a dispersing element, preferable diffraction grating,
spatially dispersing a portion of the continuum of light predestined for analysis with separate spectrum analyzing systems into a dispersed spectrum of component wavelengths in each selected part,
forming of dispersed light in each part into light beam suitable for detection with a suitable array of photodetectors,
the arrays of the photodetectors taking measurement of dispersed light in selected part or whole AV/NIR spectral range and at least one or more arrays applied for measurements of at least selected part or whole LWNIR spectral range.
Preferably these measurements are taken simultaneously or sequentially, or in any combination thereof. The measurement results are transferred to a microprocessor, and the concentration level of said at least one constituent of the sample, in particular of said blood or tissue is calculated and a result of each concentration level is produced.
According to another embodiment of the invention, there is provided a non-invasive device measuring concentration levels of constituents occurring in the sample in particular in blood and tissue in a subject such as a human or animal uses one or more radiation sources. The broad spectrum of light in the adjacent visible spectrum and near infrared range provided by the radiation or light source(s) is/are powered by one or a required number of stabilized power sources . The device (or devices) has a receptor shaped so that a sample or a part of the subject can be placed in contact with the receptor. The receptor has means for eliminating extraneous light and is located relative to the light source (or sources) so that when a sample or body part (or tissue) is placed in contact with the receptor, the source(s) can be activated and light with continuum of wavelengths, is directed onto the part. The device is equipped with means for collecting light in the AV/NIR and LWNIR spectral regions after the light has been directed onto the sample or the part. There are also means for dispersing the collected light over said broad spectrum into a dispersed spectrum of component wavelengths and means for taking measurements of a light signal at many different wavelengths in the AV/NIR and LWNIR regions simultaneously or sequentially. There are also means for transforming results of these measurements over the dispersed spectrum into the concentration of at least one constituent by using a calibration equation for the at least one constituent. There are also means for determining the concentration level of the at least one constituent of said blood or tissue and then producing a result for each concentration level determined.
According to one embodiment of the present invention there is provided a method for determining a concentration of a constituent in a sample comprising the steps of:
irradiating the sample with a continuum of wavelengths from the adjacent visible and near infrared (AV/NIR) region;
collecting radiation after the radiation has been directed onto the part;
dispersing the continuum of collected radiation into a dispersed spectrum of component wavelengths onto a detector, the detector taking measurements of at least one of transmitted or reflected radiation from the collected radiation; and transferring the measurements to a processor;
irradiating the sample with a continuum of wavelengths in the longer wavelength near infrared (LWNIR) region; detecting one or more bands of radiation after the radiation has been directed onto the sample with a detector, the detector taking measurements of at least one of transmitted or reflected radiation; and
transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms, the processor calculating the concentration of said constituent in said sample, preferably one or more separate energy sources are used to provide radiation.
According to another embodiment of the method of the invention the detector of the AV/NIR is one or more spectral instruments with an array of silicon detectors and the detector of LWNIR is one or more spectral instruments with a separate array of infrared sensitive detectors for each band of radiation.
According to yet another embodiment the detector of the AV/NIR is one or more spectral instruments with an array of silicon detectors and the detector of LWNIR is one or more spectral instruments with an array of infrared sensitive detectors and measurements for each band of radiation are taken from appropriate members of the array of infrared sensitive detectors, preferably the infrared sensitive detectors are InGaAs detectors.
According to another embodiment the spectrometers with silicon detectors arrays register light in the all of the visible, visible/infrared and adjacent to visible infrared ranges within the spectral sensitivity range of the detectors, and preferably the spectrometers with infrared sensitive detectors register light in the separate infrared ranges within their spectral sensitivity range.
According to another embodiment of the method all detectors register light in their respectable sensitivity ranges virtually simultaneously.
In another aspect of the present invention there is provided a method for determining a concentration of a constituent in a sample comprising the steps of:
irradiating the sample with a continuum of wavelengths from the AV/NIR region;
collecting radiation after the radiation has been directed onto the part;
dispersing the continuum of collected radiation into a dispersed spectrum of component wavelengths onto a detector, the detector taking measurements of at least one of transmitted or reflected radiation from the collected radiation; and transferring the measurements to a processor;
irradiating the sample with one or more bands of wavelengths in the LWNIR region; detecting the one or more bands of radiation after the radiation has been directed onto the sample with a detector, the detector taking measurements of at least one of transmitted or reflected radiation; and
transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms, the processor calculating the concentration of said constituent in said sample, preferably one or more separate energy sources are used to provide radiation.
According to another embodiment of the method of the invention the detector of the AV/NIR is one or more spectral instruments with an array of silicon detectors and the detector of LWNIR is one or more spectral instruments with a separate array of infrared sensitive detectors for each band of radiation.
According to yet another embodiment the detector of the AV/NIR is one or more spectral instruments with an array of silicon detectors and the detector of LWNIR is one or more spectral instruments with an array of infrared sensitive detectors and measurements for each band of radiation are taken from appropriate members of the array of infrared sensitive detectors, preferably the infrared sensitive detectors are InGaAs detectors.
According to another embodiment the spectrometers with silicon detectors arrays register light in the all of the visible, visible/infrared and adjacent to visible infrared ranges within the spectral sensitivity range of the detectors, and preferably the spectrometers with infrared sensitive detectors register light in the separate infrared ranges within their spectral sensitivity range.
According to another embodiment of the method all detectors register light in their respectable sensitivity ranges virtually simultaneously.
In yet another aspect of the present invention there is provided a method for determining a concentration of a constituent in a sample comprising the steps of:
irradiating the sample with a continuum of wavelengths from the AV/NIR region;
collecting radiation after the radiation has been directed onto the part;
dispersing the continuum of collected radiation into a dispersed spectrum of component wavelengths onto a detector, the detector taking measurements of at least one of transmitted or reflected radiation from the collected radiation; and transferring the measurements to a processor;
irradiating the sample with a continuum of wavelengths from the LWNIR region; collecting radiation after the radiation has been directed onto the part;
dispersing the continuum of collected radiation into a dispersed spectrum of bands of radiation onto a detector, the detector taking measurements of at least one of transmitted or reflected radiation; and
transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms, the processor calculating the concentration of said constituent in said sample, preferably one or more separate energy sources are used to provide radiation.
According to another embodiment of the method of the invention the detector of the AV/NIR is one or more spectral instruments with an array of silicon detectors and the detector of LWNIR is one or more spectral instruments with a separate array of infrared sensitive detectors for each band of radiation.
According to yet another embodiment the detector of the AV/NIR is one or more spectral instruments with an array of silicon detectors and the detector of LWNIR is one or more spectral instruments with an array of infrared sensitive detectors and measurements for each band of radiation are taken from appropriate members of the array of infrared sensitive detectors, preferably the infrared sensitive detectors are InGaAs detectors.
According to another embodiment the spectrometers with silicon detectors arrays register light in the all of the visible, visible/infrared and adjacent to visible infrared ranges within the spectral sensitivity range of the detectors, and preferably the spectrometers with infrared sensitive detectors register light in the separate infrared ranges within their spectral sensitivity range.
According to another embodiment of the method all detectors register light in their respectable sensitivity ranges virtually simultaneously.
In accordance with a preferred embodiment of any of the forgoing methods the sample is a finger of a subject.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.